1. Field of the Invention
The present invention relates generally to the fields of molecular neurology and animal models of pain. More specifically, the present invention discloses a sheep model of neuropathic pain behavior and uses thereof.
2. Description of the Related Art
The prevalence of chronic pain is common and will continue to grow due to the increase in the aging population. Chronic pain consists of either nociceptive or neuropathic pain or both. Neuropathic pain is caused by a lesion in the peripheral nerve and/or dysfunction of the central nervous system which produces symptoms often described by patients as burning, tingling, hot stabbing and shock-like in the absence of nociceptive stimulus.
There are many causes of neuropathic pain. Even though there is no universal classification system, neuropathic pain can be divided into categories based on etiologies and anatomy such as trauma (spinal cord injury, amputation), infection (herpes zoster, HIV), and compression syndromes (radiculopathy, carpel tunnel)1. Diagnosis based treatments have shown relative effective relief of neuropathic pain based on randomized controlled trials2. Application of results showing successful treatment of one etiology of neuropathic pain hasn't been reliably applied to another. A survey of 602 patients with neuropathic pain reported that these patients visited their physician more frequently reporting substantial pain interfering with their daily functioning despite receiving treatment3. Evidence suggests that the current diagnosis based treatments for neuropathic pain conditions are inadequate.
An increasing interest in pain research has been to develop treatments of neuropathic pain based on mechanisms instead of a diagnostic approach4, 5. A mechanistic approach might provide more effective treatments. Much of the current knowledge of the mechanisms of neuropathic pain is based on animal models. Established animals models used in preclinical trials include selective spinal nerve ligation, sciatic loose ligature model, or spared nerve injury of the sciatic nerve in rat6-8. These rat models provide an economical way to elucidate pathways and mechanisms of neuropathic pain.
Although the rat models might be limited in predicting efficacy and safety in clinical trials because of several factors: the size difference between rats and humans, the lack of genetic diversity of inbred strains, and the relatively short lives which might limit the measurement of longitudinal effects. However, lack of available large mammalian model limits the ability to study efficacy and safety of therapeutic alternatives prior to clinical trials.
The sheep as a large-scale animal is advantageous due to its docile behavior, available and economical husbandry, and relative ease of training. The sheep is an attractive animal model for several reasons. Sheep have been used in research since the 1600's. Researchers have used sheep to study fetology, scrapie, asthma, viral diarrhea, spinal hardware, intrathecal drug delivery, and acute pain models.
In 1975, one of the first researchers to describe a method to quantify the mechanical stimuli in sheep was Lebeaux9. He described a method to measure the behavioral response to mechanical stimuli in restrained sheep. This method involved placing the sheep in a sling, which allowed movement of the legs and delivering a pinch with allis forceps to specific dermatomes. The response was limb withdrawal and/or a sign of generalized sensation and this was used to assess sensory loss produced by intrathecal or epidural local anesthetics. This study showed that pain and sensation could be qualitatively measured but failed to quantify the behavioral response. This failure was most likely due to a non-reproducible stimulus. Therefore, this method is only suitable for describing the gross changes in sensation.
Another sheep model described a method of delivering a quantifiable mechanical stimulus10. The mechanical stimulus was delivered by a device that utilizes pneumatic-driven pins to place pressure on the distal forelimbs and the evoked response was a forelimb withdrawal. A major disadvantage of this method is that it requires a fabricated device to produce pressure on forelimbs, which might increase variability among researchers. Another disadvantage is that the acute pain state was brief and required re-stimulation for each behavior measurement.
Sheep models have also been used to study spine stabilizing hardware, pharmacology of implantable intrathecal delivery devices, and nociceptive pain10-12. Sheep models have also been used extensively to study intrathecal drug delivery in pre-clinical trials. Since the size of the sheep spine is similar to humans, this also allows the use of commercially available intrathecal drug delivery devices.